EP0035925A1 - 3-Chloroquinoline derivatives, processes for their preparation and medicaments containing them - Google Patents
3-Chloroquinoline derivatives, processes for their preparation and medicaments containing them Download PDFInfo
- Publication number
- EP0035925A1 EP0035925A1 EP81400283A EP81400283A EP0035925A1 EP 0035925 A1 EP0035925 A1 EP 0035925A1 EP 81400283 A EP81400283 A EP 81400283A EP 81400283 A EP81400283 A EP 81400283A EP 0035925 A1 EP0035925 A1 EP 0035925A1
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- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- formula
- group
- alkyl
- ppm
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 23
- 150000005647 3-chloroquinolines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000003277 amino group Chemical group 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- -1 useful as hypnotic Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000001961 anticonvulsive agent Substances 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 230000000147 hypnotic effect Effects 0.000 claims description 4
- 150000002475 indoles Chemical class 0.000 claims description 4
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical class Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 claims description 3
- 150000004678 hydrides Chemical class 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims 2
- 230000001773 anti-convulsant effect Effects 0.000 claims 1
- 229960003965 antiepileptics Drugs 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical group 0.000 abstract 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 52
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 7
- 229960003529 diazepam Drugs 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 150000001557 benzodiazepines Chemical class 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940049706 benzodiazepine Drugs 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940125681 anticonvulsant agent Drugs 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000003326 hypnotic agent Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- YALYLPKSKBQFJP-UHFFFAOYSA-N chloroform;n-ethylethanamine Chemical compound ClC(Cl)Cl.CCNCC YALYLPKSKBQFJP-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- XNMYNYSCEJBRPZ-UHFFFAOYSA-N 2-[(3-butyl-1-isoquinolinyl)oxy]-N,N-dimethylethanamine Chemical compound C1=CC=C2C(OCCN(C)C)=NC(CCCC)=CC2=C1 XNMYNYSCEJBRPZ-UHFFFAOYSA-N 0.000 description 1
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 description 1
- WQKHERPPDYPMNX-UHFFFAOYSA-N 6-chloro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(Cl)=CC=C21 WQKHERPPDYPMNX-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VQXZAMQCXABWTG-UHFFFAOYSA-N Cc1c(C2CC2)c(-c2ccccc2)nc2c1cccc2 Chemical compound Cc1c(C2CC2)c(-c2ccccc2)nc2c1cccc2 VQXZAMQCXABWTG-UHFFFAOYSA-N 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CSDVBKMWJXRLEG-UHFFFAOYSA-N N1CC(CCC1)CC(=O)CC1CNCCC1 Chemical compound N1CC(CCC1)CC(=O)CC1CNCCC1 CSDVBKMWJXRLEG-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UPBWIICFGYMCPC-UHFFFAOYSA-N bis(2-methoxyethoxy)aluminum Chemical compound COCCO[Al]OCCOC UPBWIICFGYMCPC-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Definitions
- the present invention relates to new 3-chloro quinoline derivatives which can be used as medicaments.
- X is fixed in position 5, 6, 7 or 8 on the quinoline ring and represents a hydrogen or halogen atom (chlorine, fluorine, bromine, iodine) or an alkyl, alkoxy or alkylthio group having 1 with 4 carbon atoms,
- one of the substituents R1 and R 2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group substituted by one or two substituents taken from the halogen atoms (chlorine, fluorine, bromine, iodine), the alkyl, alkoxy or alkylthio groups having 1 to 4 carbon atoms, the trifluoromethyl group, the nitro group, the amino group and the amino group substituted by one or two alkyl groups having 1 or 2 atoms carbon, and the other is a piperidylalkyl group of formula: where n is an integer equal to 1, 2 or 3, R is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and the radical (CH2) n is attached in position 2, 3 or 4 on the piperidine ring.
- halogen atoms chlorine, fluorine, bromine, iodine
- X is preferably a hydrogen atom
- R 2 is preferably a hydrogen atom or a methyl or phenyl group
- R 1 is preferably a group of formula:
- R ' 2 and R' 1 represent a hydrogen atom , an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group substituted by one or two substituents chosen from halogen atoms, alkyl, alkoxy or alkylthio groups having 1 to 4 carbon atoms, CF 3 , NO 2 , NH 2 and the amino group substituted by one or two alkyl groups having 1 or 2 carbon atoms.
- indole derivatives of formulas (II) and (IIa) are known compounds or which can be prepared by known methods (cf. for example: DeGraw et al, J. Heterocyclic Chem. 3 (1) , 67-69, 1966; Tacconi et al, Farmaco (Pavia), Ed. Sci. 20 (7), 470-481, 1965; Gray et al, Journal of Organic Chemistry, 26, 3368-3372, 1961; English patent 1,023,781; French patent for medicine 1693 M; French patent 2,334,358).
- reactions (1) and (lbis) is prepared "in situ" by the action of a base on chloroform.
- Reactions (1) and (ibis) can advantageously be carried out by stirring a solution or a suspension of the indole derivative of formula (II) or (II bis) in chloroform with an aqueous solution of sodium hydroxide (in particular a solution aqueous at 50% sodium hydroxide), in the presence of a quaternary ammonium salt such as benzyltriethylammonium chloride for example.
- the hydrolysis reaction (2) can be carried out by heating, preferably at boiling point, the intermediate compound of formula (III) or (III bis) in an aqueous solution of an acid such as hydrochloric acid or l 'sulfuric acid.
- the compounds of general formula (I) for which R is an alkyl group can be prepared by the action of an alkylating agent, such as an alkyl halide of formula RC1 or RBr, on the corresponding compounds of formula (I) for which R is a hydrogen atom:
- an alkylating agent such as an alkyl halide of formula RC1 or RBr
- the alkylation reaction is carried out according to methods known per se (cf. RB Wagner and HD Zook, Synthetic Organic Chemistry, p. 666, J. Wiley and Sons, 1965). It is advantageously carried out in the presence of an organic or inorganic base (for example sodium or potassium carbonate) in an inert solvent such as dimethylformamide.
- the compounds of general formula (I) for which R is an alkyl group are preferably prepared by a two-step process which consists in reacting in a first time the corresponding compounds of formula (1) for which R is a hydrogen atom with a compound of formula in which Z represents an alkyl group having 1 to 3 carbon atoms or a low alkoxy group (for example methoxy or ethoxy), and then reducing by means of a hydride the compounds of formula (IV) or (IV bis) thus obtained.
- the reaction scheme is as follows:
- R ' 1 and R' 2 have the meanings indicated above, and X and n have the same meanings as in formula (I).
- Reaction (4) also uses known methods (cf. for example R.B. Wagner and H.D. Zook, Synthetic Organic Chemistry, p. 660, J. Wiley and Sons, 1953).
- reducing hydride aluminum hydride and lithium or other complex hydrides such as sodium hydride and bis (2-methoxyethoxy) aluminum, in an inert solvent such as ether or an aromatic hydrocarbon.
- the group -CO-Z is transformed into a group -CH2-Z in the case where Z is an alkyl group, and into a methyl group in the case where Z is a low alkoxy group.
- reaction mixtures obtained by the various processes described above are treated according to conventional, physical (evaporation, extraction using a solvent, distillation, crystallization, chromatography, etc.) or chemical (salt formation and regeneration) methods. base, etc.) in order to isolate the compounds of formula (I) in the pure state.
- the compounds of formula (I) in the form of the free base can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid in an appropriate solvent.
- Benzodiazepine class drugs are used as anticonvulsants, hypnotics and for the treatment of anxiety states and various psychoneurotic states.
- the presence of specific benzodiazepine receptors in the membranes of the rat brain has been demonstrated [SQUIRES et al., Nature, 266, (1977), 732J and the degree of affinity of benzodiazepines for these receptors, degree of affinity measured by their ability to displace tritiated Diazepam from its binding sites is in good correlation with the pharmacodynamic effects observed in animals and in humans.
- the products of the invention although of different structure from those of benzodiazepines, displace Diazepam from its binding sites. They can therefore find applications as hypnotics, as anticonvulsants, and in the treatment of states of tension and anxiety resulting from "stressful" circumstances or somatic disorders linked to emotional factors. They can be used for the treatment of psychoneurotic states manifested by symptoms of anxiety, apprehension, fatigue, agitation or depression.
- the following examples illustrate the invention without limiting it.
- the data relating to nuclear magnetic resonance spectra (abbreviated: R.M.N. spectra) appearing in these examples relate to the nuclear magnetic resonance of the protons of the compounds in the basic state.
- R.M.N. spectra The reference used is tetramethylsilane.
- Example 2 The procedure is as in Example 1, starting with 8.3 g of (indolyl-2) -2 ethyl] -4 piperidine and 0.18 g of triethylbenzylammonium chloride in 90 ml of chloroform, and 11 g of sodium hydroxide dissolved in 22 ml of water. 1.45 g of chloro-3 [(piperidyl-4) -2 ethyl] -2 quino - leine are obtained, the monohydrochloride melts at 162 ° C.
- Example 2 The procedure is as in Example 1, starting with 3.8 g of [(indolyl-3) -2 ethyl] -3 piperidine and 0.075 g of benzyltriethylammonium chloride in 40 ml of chloroform, and 5 g of sodium hydroxide in 10 ml of water. 1.3 g of chloro-3 [(piperidyl-3) -2 ethyl] -4 quinoline are finally obtained, in the form of monohydrochloride dihydrate, melting at 75 ° C.
- Indolyl-3 (3-piperidyl methyl) ketone can be prepared by the process described in French patent 2,334,358.
- 0.38 g of aluminum and lithium hydride are gradually introduced, in portions, into 20 ml of dry tetrahydrofuran, under a nitrogen atmosphere.
- the suspension obtained is cooled to 0 ° C., then a solution of 1.6 g of 3-chloro-6-methoxy-6 [(ethoxycarbonyl-1-piperidyl-4) -2 ethyl] -4 quinoline is added dropwise. in tetrahydrofuran.
- the reaction medium is maintained for 3 hours in an ice bath, then 0.45 ml of water, 0.33 ml of a 5N aqueous sodium hydroxide solution and very slowly and in order are added. ml of water.
- C represents the concentration of 3 H Diazepam
- K an affinity constant equal to 2.74 ⁇ M
- IC 50 the concentration necessary to obtain a 50% inhibition of the binding of 3 H Diazepam.
- the acute toxicities of the compounds according to the invention were determined in the male CD 1 mouse (Charles RIVER) orally.
- the LD50s were calculated, after 3 days of observation, by the cumulative method of JJ REED and H. MUENCH (Amer. J. Hyg. 1938, 27, 493).
- the compounds according to the invention behave like relatively non-toxic substances in mice, since the LD50 of the compounds are between 200 and 1000 mg / kg.
- the compounds of the invention and their pharmaceutically acceptable salts can be used in human therapy, in the form of tablets, capsules, capsules, suppositories, ingestible or injectable solutions, etc. as hypnotics, anticonvulsants and for the treatment of states of anxiety and various psychoneurotic states.
- the dosage depends on the desired effects and the route of administration used. For example, orally, it can be between 5 and 250 mg of active substance per day, with unit doses ranging from 1 to 50 mg.
Abstract
Composés, utiles comme médicaments, de formule: <IMAGE> dans laquelle X est hydrogène, halogène, alkyle 1-4 C, alcoxy 1-4 C ou alkylthio 1-4 C, l'un des substituants R1 et R2 est hydrogène, alkyl 1-4 C, phényle ou phényle substitué par halogène, alkyle 1-4 C, alcoxy 1-4 C, alkylthio 1-4 C, CF3, NO2, NH2 ou amino substitué par un ou deux groupes alkyle 1-2 C, et l'autre est un groupe de formule <IMAGE> dans laquelle n est 1,2 ou 3 et R est hydrogène ou alkyle 1-4 C.Compounds, useful as medicaments, of formula: <IMAGE> in which X is hydrogen, halogen, 1-4 C alkyl, 1-4 C alkoxy or 1-4 C alkylthio, one of the substituents R1 and R2 is hydrogen, alkyl 1-4 C, phenyl or phenyl substituted by halogen, 1-4 C alkyl, 1-4 C alkoxy, 1-4 C alkylthio, CF3, NO2, NH2 or amino substituted by one or two 1-2 C alkyl groups, and the other is a group of formula <IMAGE> in which n is 1,2 or 3 and R is hydrogen or 1-4 C alkyl.
Description
La présente invention a pour objet de nouveaux dérivés de la chloro-3 quinoléine utilisables comme médicaments.The present invention relates to new 3-chloro quinoline derivatives which can be used as medicaments.
Ces dérivés peuvent être représentés par la formule générale:
l'un des substituants R1 et R2 est un atome d'hydrogène, un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe phényle ou un groupe phényle substitué par un ou deux substituants pris parmi les atomes d'halogène (chlore, fluor, brome, iode), les groupes alkyle, alcoxy ou alkylthio ayant 1 à 4 atomes de carbone, le groupe trifluorométhyle, le groupe nitro, le groupe amino et le groupe amino substitué par un ou deux groupes alkyle ayant 1 ou 2 atomes de carbone, et l'autre est un groupe pipéridylalkyle de formule :
Dans la formule (I) précédente, X est de préférence un atome d'hydrogène, R2 est de préférence un atome d'hydrogène ou un groupe méthyle ou phényle, et R1 est de préférence un groupe de formule :
Les composés de formule générale (I) pour lesquels R est un atome d'hydrogène peuvent être préparés par action du dichlorocarbène : CC12 sur les dérivés de l'indole de formule (II) ou (II bis) et hydrolyse des dérivés N-formylés de formule (III) ou (III bis) ainsi obtenus, selon le schéma réactionnel suivant :
Dans les formules (II), (II bis), (III) et (III bis), X et n ont les mêmes significations que dans la formule (I), et R'2 et R'1 représentent un atome d'hydrogène, un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe phényle ou un groupe phényle substitué par un ou deux substituants pris parmi les atomes d'halogène, les groupes alkyle, alcoxy ou alkylthio ayant 1 à 4 atomes de carbone, CF3, N02, NH2 et le groupe amino substitué par un ou deux groupes alkyle ayant 1 ou 2 atomes de carbone.In formulas (II), (II bis), (III) and (III bis), X and n have the same meanings as in formula (I), and R ' 2 and R' 1 represent a hydrogen atom , an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group substituted by one or two substituents chosen from halogen atoms, alkyl, alkoxy or alkylthio groups having 1 to 4 carbon atoms, CF 3 , NO 2 , NH 2 and the amino group substituted by one or two alkyl groups having 1 or 2 carbon atoms.
Les dérivés de l'indole de formules (II) et (II bis) sont des composés connus ou que l'on peut préparer par des procédés connus (cf. par exemple : DeGraw et al, J. Heterocyclic Chem. 3 (1), 67-69, 1966 ; Tacconi et al, Farmaco (Pavia), Ed. Sci. 20(7), 470-481, 1965 ; Gray et al, Journal of Organic Chemistry, 26, 3368-3372, 1961 ; brevet anglais 1 023 781 ; brevet français de médicament 1693 M ; brevet français 2 334 358).The indole derivatives of formulas (II) and (IIa) are known compounds or which can be prepared by known methods (cf. for example: DeGraw et al, J. Heterocyclic Chem. 3 (1) , 67-69, 1966; Tacconi et al, Farmaco (Pavia), Ed. Sci. 20 (7), 470-481, 1965; Gray et al, Journal of Organic Chemistry, 26, 3368-3372, 1961; English patent 1,023,781; French patent for medicine 1693 M; French patent 2,334,358).
Le dichlorocarbène utilisé dans les réactions (1) et (lbis) est préparé "in situ" par action d'une base sur le chloroforme. Les réactions (1) et(ibis) peuvent être réalisées avantageusement en agitant une solution ou une suspension du dérivé indolique de formule (II) ou (II bis) dans le chloroforme avec une solution aqueuse d'hydroxyde de sodium (en particulier une solution aqueuse à 50% d'hydroxyde de sodium), en présence d'un sel d'ammonium quaternaire tel que le chlorure de benzyltriéthylammonium par exemple.The dichlorocarbene used in reactions (1) and (lbis) is prepared "in situ" by the action of a base on chloroform. Reactions (1) and (ibis) can advantageously be carried out by stirring a solution or a suspension of the indole derivative of formula (II) or (II bis) in chloroform with an aqueous solution of sodium hydroxide (in particular a solution aqueous at 50% sodium hydroxide), in the presence of a quaternary ammonium salt such as benzyltriethylammonium chloride for example.
La réaction d'hydrolyse (2) peut être effectuée par chauffage, de préférence à l'ébullition, du composé intermédiaire de formule (III) ou (III bis) dans une solution aqueuse d'un acide tel que l'acide chlorhydrique ou l'acide sulfurique.The hydrolysis reaction (2) can be carried out by heating, preferably at boiling point, the intermediate compound of formula (III) or (III bis) in an aqueous solution of an acid such as hydrochloric acid or l 'sulfuric acid.
Les composés de formule générale (I) pour lesquels R est un groupe alkyle peuvent être préparés par action d'un agent alkylant, tel qu'un halogénure d'alkyle de formule RC1 ou RBr, sur les composés correspondants de formule (I) pour lesquels R est un atome d'hydrogène: La réaction d'alkyla- tion est effectuée selon des procédés connus en soi (cf. R.B. Wagner et H.D. Zook, Synthetic Organic Chemistry, p. 666, J. Wiley and Sons, 1965). On opère avantageusement en présence d'une base organique ou minérale (par exemple le carbonate de sodium ou de potassium) au sein d'un solvant inerte tel que le diméthylformamide.The compounds of general formula (I) for which R is an alkyl group can be prepared by the action of an alkylating agent, such as an alkyl halide of formula RC1 or RBr, on the corresponding compounds of formula (I) for which R is a hydrogen atom: The alkylation reaction is carried out according to methods known per se (cf. RB Wagner and HD Zook, Synthetic Organic Chemistry, p. 666, J. Wiley and Sons, 1965). It is advantageously carried out in the presence of an organic or inorganic base (for example sodium or potassium carbonate) in an inert solvent such as dimethylformamide.
Les composés de formule générale (I) pour lesquels R est un groupe alkyle sont préparés de préférence par un procédé en deux étapes qui consiste à faire réagir dans un premier temps les composés correspondants de formule (1) pour lesquels R est un atome d'hydrogène avec un composé de formule
Dans les formules intervenant dans le schéma réactionnel ci-dessus, R'1 et R'2 ont les significations indiquées précédemment, et X et n ont les mêmes significations que dans la formule (I).In the formulas involved in the reaction scheme above, R ' 1 and R' 2 have the meanings indicated above, and X and n have the same meanings as in formula (I).
Pour effectuer les réactions (3) et (3) bis, on utilise des méthodes, connues en soi, qui permettent de transformer une amine secondaire en amide (cas Z = alkyle) ou en carbamate (cas Z = alcoxy), par exemple celles décrites par R.B. Wagner et H.D. Zook (Synthetic Organic Chemistry, p. 565 et p. 646, J. Wiley and Sons, 1953). On opère-généralement en présence d'une base telle que l'hydroxyde de sodium en solution aqueuse ou la triéthylamine, au sein d'un solvant inerte tel que le chloroforme ou le trichlo- ro-1,1,1 éthane, à une température comprise entre O°C et 30°C.To carry out reactions (3) and (3) bis, methods known per se are used which make it possible to transform a secondary amine into an amide (case Z = alkyl) or into a carbamate (case Z = alkoxy), for example those described by RB Wagner and HD Zook (Synthetic Organic Chemistry, p. 565 and p. 646, J. Wiley and Sons, 1953). The operation is generally carried out in the presence of a base such as sodium hydroxide in aqueous solution or triethylamine, in an inert solvent such as chloroform or trichloro-1,1,1 ethane, at a temperature between O ° C and 30 ° C.
La réaction (4) utilise également des méthodes connues (cf. par exemple R.B. Wagner et H.D. Zook, Synthetic Organic Chemistry, p. 660, J. Wiley and Sons, 1953). On utilise avantageusement comme hydrure réducteur l'hydrure d'aluminium et de lithium ou d'autres hydrures complexes tels que l'hydrure de sodium et de bis (méthoxy-2 éthoxy) aluminium, au sein d'un solvant inerte tel qu'un éther ou un hydrocarbure aromatique. Dans la réaction (4) le groupe -CO-Z est transformé en groupe -CH2-Z dans le cas où Z est un groupe alkyle, et en groupe méthyle dans le cas où Z est un groupe alcoxy bas.Reaction (4) also uses known methods (cf. for example R.B. Wagner and H.D. Zook, Synthetic Organic Chemistry, p. 660, J. Wiley and Sons, 1953). Advantageously used as reducing hydride aluminum hydride and lithium or other complex hydrides such as sodium hydride and bis (2-methoxyethoxy) aluminum, in an inert solvent such as ether or an aromatic hydrocarbon. In reaction (4) the group -CO-Z is transformed into a group -CH2-Z in the case where Z is an alkyl group, and into a methyl group in the case where Z is a low alkoxy group.
Les mélanges réactionnels obtenus par les divers procédés décrits précédemment sont traités suivant des méthodes classiques, physiques (évaporation, extraction à l'aide d'un solvant, distillation, cristallisation, chromatographie, etc...) ou chimiques (formation de sel et régénération de la base, etc...) afin d'isoler les composés de formule (I) à l'état pur.The reaction mixtures obtained by the various processes described above are treated according to conventional, physical (evaporation, extraction using a solvent, distillation, crystallization, chromatography, etc.) or chemical (salt formation and regeneration) methods. base, etc.) in order to isolate the compounds of formula (I) in the pure state.
Les composés de formule (I) sous forme de base libre peuvent éventuellement être transformés en sels d'addition avec un acide minéral ou organique par action d'un tel acide au sein d'un solvant approprié.The compounds of formula (I) in the form of the free base can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid in an appropriate solvent.
Les médicaments de la classe des benzodiazépines sont utilisés comme anticonvulsivants, comme hypnotiques et pour le traitement des états d'anxiété et de divers états psychonévrotiques. La présence de récepteurs spécifiques des benzodiazépines dans les membranes de cerveau de rat a été démontrée [SQUIRES et Coll., Nature, 266, (1977), 732J et le degré d'affinité des benzodiazépines pour ces récepteurs, degré d'affinité mesuré par leur aptitude à déplacer de ses sites de liaison le Diazépam tritié, est en bonne corrélation avec les effets pharmacodynamiques observés chez l'animal et chez l'homme.Benzodiazepine class drugs are used as anticonvulsants, hypnotics and for the treatment of anxiety states and various psychoneurotic states. The presence of specific benzodiazepine receptors in the membranes of the rat brain has been demonstrated [SQUIRES et al., Nature, 266, (1977), 732J and the degree of affinity of benzodiazepines for these receptors, degree of affinity measured by their ability to displace tritiated Diazepam from its binding sites is in good correlation with the pharmacodynamic effects observed in animals and in humans.
Jusqu'à ce jour, en dehors des benzodiazépines, aucun médicament agissant par ailleurs sur le système nerveux central ne s'est montré capable de déplacer, de manière significative, le Diazépam de ses sites de liaison [cf, BRAESTRUP et Coll., Europ. J. Pharmacol. 48, (1978) 26].To date, apart from benzodiazepines, no drug acting otherwise on the central nervous system has been shown to be able to significantly displace Diazepam from its binding sites [cf, BRAESTRUP et al., Europ . J. Pharmacol. 48, (1978) 26].
Les produits de l'invention, bien que de structure différente de celles des benzodiazépines, déplacent le Diazépam de ses sites de liaison. Ils peuvent donc trouver des applications comme hypnotiques, comme anticonvulsivants, et dans le traitement des états de tension et d'anxiété résultant de circonstances "stressantes" ou de troubles somatiques liés à des facteurs émotionnels. Ils sont utilisables pour le traitement des états psychonévrotiques se manifestant par des symptômes d'anxiété, d'appréhension, de fatigue, d'agitation ou de dépression.The products of the invention, although of different structure from those of benzodiazepines, displace Diazepam from its binding sites. They can therefore find applications as hypnotics, as anticonvulsants, and in the treatment of states of tension and anxiety resulting from "stressful" circumstances or somatic disorders linked to emotional factors. They can be used for the treatment of psychoneurotic states manifested by symptoms of anxiety, apprehension, fatigue, agitation or depression.
Les exemples suivants illustrent l'invention sans la limiter. Les données relatives aux spectres de résonance magnétique nucléaire (en abrégé : spectres R.M.N.) figurant dans ces exemples concernent la résonance magnétique nucléaire des protons des composés à l'état de base. Pour effectuer les mesures de résonance magnétique nucléaire, les composés sont mis en solution dans le chloroforme deutéré. La référence utilisée est le tétraméthylsilane.The following examples illustrate the invention without limiting it. The data relating to nuclear magnetic resonance spectra (abbreviated: R.M.N. spectra) appearing in these examples relate to the nuclear magnetic resonance of the protons of the compounds in the basic state. To carry out nuclear magnetic resonance measurements, the compounds are dissolved in deuterated chloroform. The reference used is tetramethylsilane.
A une suspension bien agitée de 45,8 g d' [(indolyl-3)-2 éthyl] -4 pipéridine et 1 g de chlorure de benzyltriéthylammonium dans 500 ml de chloroforme exempt d'éthanol, on ajoute lentement, en deux heures, en maintenant à la température ambiante (environ 20°C), une solution de 60 g d'hydroxyde de sodium dans 120 ml d'eau. La dissolution est progressive. Après 72 heures à température ambiante, on sépare les deux phases par décantation. La phase aqueuse est extraite par deux fois 100 ml de chloroforme. Les phases organiques sont rassemblées et concentrées par élimination du chloroforme.To a well-stirred suspension of 45.8 g of [(indolyl-3) -2 ethyl ] -4 piperidine and 1 g of benzyltriethylammonium chloride in 500 ml of ethanol-free chloroform, slowly added over two hours, now at room temperature (about 20 ° C), a solution of 60 g of sodium hydroxide in 120 ml of water. The dissolution is progressive. After 72 hours at room temperature, the two phases are separated by decantation. The aqueous phase is extracted with twice 100 ml of chloroform. The organic phases are combined and concentrated by elimination of the chloroform.
Le résidu obtenu est chauffé au reflux pendant une heure dans 400 ml d'une solution aqueuse 5N d'acide chlorhydrique. Après refroidissement à 0°C, on alcalinise au moyen de 250 ml d'une solution aqueuse ION d'hydroxyde de sodium, puis on extrait par 300 ml de chloroforme. La phase organique est lavée par 500 ml d'eau, séchée sur sulfate de magnésium, puis concentrée par élimination du chloroforme. On obtient ainsi 61,2 g d'un produit huileux. Ce produit est fixé sur colonne de silice, puis on élue par un mélange chloroforme-diéthylami- ne
Spectre R.M.N. du produit obtenu :
- Les déplacements chimiques odes protons sont les suivants :
- - aromatiques δ: 7,3 - 8,8 ppm
- - CH2-N et CH2-Ar δ: 2,3 - 3,4 ppm
- The chemical displacements of the protons are as follows:
- - aromatic δ: 7.3 - 8.8 ppm
- - CH 2 -N and CH 2 -Ar δ: 2.3 - 3.4 ppm
On opère comme à l'exemple 1, en partant de 11 g de [(chloro-5 indolyl-3)-2 éthyl ] -4 pipéridine et 0,21 g de chlorure de benzyltriéthylammonium en suspension dans 100 ml de chloroforme et de 12,5 g d'hydroxyde de sodium en solution dans 25 ml d'eau. On obtient finalement 2g de dichloro-3,6 [(pipéridyl-4)-2 éthyl ]-4 quinoléine sous forme de dichlorhydrate fondant à 248°C.The procedure is as in Example 1, starting with 11 g of [(5-chloro-indolyl-3) -2 ethyl] -4 piperidine and 0.21 g of benzyltriethylammonium chloride suspended in 100 ml of chloroform and 12 , 5 g of sodium hydroxide in solution in 25 ml of water. Finally, 2 g of dichloro-3,6 [(piperidyl-4) -2 ethyl] -4 quinoline are obtained in the form of dihydrochloride melting at 248 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ; 7,3 - 8,7 ppm
- - CH2Ar et CH2N δ: 2,5 - 3,4 ppm
- - aromatics δ; 7.3 - 8.7 ppm
- - CH 2 Ar and CH 2 N δ: 2.5 - 3.4 ppm
On opère comme à l'exemple 1, en partant de 15 g de [(méthoxy-5 indolyl-3)-2 éthyl] -4 pipéridine et 0,25 g de chlorure de triéthylbenzylammonium dans 120 ml de chloroforme et de 18 g d'hydroxyde de sodium dans 35 ml d'eau. On obtient finalement 1,85 g de chloro-3 méthoxy-6 [(pipéridyl-4)-2 éthyl]-4 quinoléine, sous forme de dichlorhydrate fondant à 210°C.The procedure is as in Example 1, starting with 15 g of [(5-methoxy-indolyl-3) -2 ethyl] -4 piperidine and 0.25 g of triethylbenzylammonium chloride in 120 ml of chloroform and 18 g of sodium hydroxide in 35 ml of water. 1.85 g of 3-chloro-6-methoxy [(piperidyl-4) -2 ethyl] -4 quinoline are finally obtained in the form of the dihydrochloride melting at 210 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,1 - 8,7 ppm
- - CH2N et CH2Ar δ: 2,2 - 3,4 ppm
- - CH30 δ: 4 ppm
- - aromatic δ: 7.1 - 8.7 ppm
- - CH 2 N and CH 2 Ar δ: 2.2 - 3.4 ppm
- - CH 3 0 δ: 4 ppm
On opère comme à l'exemple 1, en partant de 5,9 g de [(méthyl-2 indolyl-3)-2 éthyl ] -4 pipéridine et 0,12 g de chlorure de triéthylbenzylammonium dans 60 ml de chloroforme et de 7,5 g d'hydroxyde de sodium dans 15 ml d'eau. On obtient finalement 2,7 g de méthyl-2 chloro-3 [(pipéridyl-4)-2 éthyl ] -4 quinoléine sous forme de monochlorhydrate qui fond à 255°C.The procedure is as in Example 1, starting with 5.9 g of [(2-methyl-indolyl-3) -2 ethyl] -4 piperidine and 0.12 g of triethylbenzylammonium chloride in 60 ml of chloroform and 7 , 5 g of sodium hydroxide in 15 ml of water. 2.7 g of methyl-2-chloro-3 [(piperidyl-4) -2 ethyl] -4 quinoline are finally obtained in the form of the monohydrochloride which melts at 255 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,4 - 8,2 ppm
- - CH3Ar δ: 2,8 ppm
- - CHZN et CH2Ar δ: 2,4 - 3,4 ppm
- - aromatic δ: 7.4 - 8.2 ppm
- - CH 3 Ar δ: 2.8 ppm
- - CH Z N and CH 2 Ar δ: 2.4 - 3.4 ppm
On opère comme à l'exemple 1, en partant de 12 g de [(phényl-2 indolyl-3)-2 éthyl] -4 pipéridine et 0,2 g de chlorure de triéthylbenzylammonium dans 110 ml de chloroforme et de 12 g d'hydroxyde de sodium dans 24 ml d'eau. On obtient finalement 1,05 g de phényl-2 chloro-3 [(pipéridyl-4) -2 éthyl -4 quinoléine sous forme de chlorhydrate fondant à 233°C.The procedure is as in Example 1, starting with 12 g of [(2-phenyl-indolyl-3) -2 ethyl] -4 piperidine and 0.2 g of triethylbenzylammonium chloride in 110 ml of chloroform and 12 g of sodium hydroxide in 24 ml of water. 1.05 g of 2-phenyl-3-chloro [(piperidyl-4) -2-ethyl-4-quinoline is finally obtained in the form of the hydrochloride, melting at 233 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,2 - 8,4 ppm
- - CH2 N et CH2Ar δ: 2,2 - 3,4 ppm
- - aromatic δ: 7.2 - 8.4 ppm
- - CH 2 N and CH 2 Ar δ: 2.2 - 3.4 ppm
La [(phényl-2 indolyl-3)-2 éthyl ]-4 pipéridine,produit de départ, a été préparée de la manière suivante :
- Une suspension bien agitée contenant 39,5 g de [(phényl-2 indolyl-3) -2 éthyl ]-4 pyridine en solution dans 40 ml d'acide acétique et 2 g d'oxyde de platine Adams est maintenue, à la température ambiante, sous une pression d'hydrogène correspondant à une surpression de 50 mm d'eau par rapport à la pression atmosphérique, jusqu'à cessation de l'absorption de gaz.
- A well-stirred suspension containing 39.5 g of [(2-phenyl-indolyl-3) -2 ethyl] -4 pyridine in solution in 40 ml of acetic acid and 2 g of Adams platinum oxide is maintained at the temperature ambient, under a hydrogen pressure corresponding to an overpressure of 50 mm of water compared to atmospheric pressure, until cessation of absorption of gas.
Le platine est ensuite séparé par filtration et la solution acétique est concentrée par évaporation. Le résidu huileux obtenu est alcalinisé par addition d'une solution aqueuse 11N d'hydroxyde de sodium et on extrait par 500 ml de chloroforme. La phase chloroformique est séchée sur sulfate de magnésium, puis concentrée par élimination du chloroforme. On obtient ainsi 37,8 g de [(phényl-2 indolyl-3)-2 éthyl] -4 pipéridine qui fond à 183°C.The platinum is then separated by filtration and the acetic solution is concentrated by evaporation. The oily residue obtained is made alkaline by adding an 11N aqueous solution of sodium hydroxide and extracted with 500 ml of chloroform. The chloroform phase is dried over magnesium sulphate, then concentrated by elimination of chlorofor me. 37.8 g of [(2-phenyl-indolyl-3) -2 ethyl] -4 piperidine are thus obtained, which melts at 183 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,2 - 7,8 ppm
- - CH2Ar et CHN δ: : 2,4 - 3,3 ppm
- - aromatic δ: 7.2 - 7.8 ppm
- - CH 2 Ar and CHN δ:: 2.4 - 3.3 ppm
La [(phényl-2 indolyl-3)-2 éthyl] -4 pyridine a été préparée selon la méthode de P. BRUNI, Ann. Chim. (ROME) 1967, 57(4), 376-81.[(2-Phenyl-indolyl-3) -2 ethyl] -4 pyridine was prepared according to the method of P. BRUNI, Ann. Chim. (ROME) 1967, 57 (4), 376-81.
On opère comme à l'exemple 1, en partant de 13,4 g d'(indolyl-3 méthyl)-4 pipéridine et 0,54 g de chlorure de triéthylbenzylammonium dans 130 ml de chloroforme et de 19,5 g d'hydroxyde de sodium en solution dans 39 ml d'eau. On obtient finalement 4,2 g de chloro-3 [(pipéridyl-4). méthyl]-4 quinoléine sous forme de dichlorhydrate fondant au-dessus de 260°C.The procedure is as in Example 1, starting with 13.4 g of (3-indolyl methyl) -4 piperidine and 0.54 g of triethylbenzylammonium chloride in 130 ml of chloroform and 19.5 g of hydroxide sodium solution in 39 ml of water. Finally, 4.2 g of chloro-3 [(piperidyl-4) are obtained. methyl] -4 quinoline in the form of dihydrochloride melting above 260 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,3 - 9 ppm
- - CH2Ar δ: 3,2 ppm
- - aromatic δ: 7.3 - 9 ppm
- - CH 2 Ar δ: 3.2 ppm
On opère comme à l'exemple 1, en partant de 10,2 g de [(méthoxy-5 indolyl-3) méthyl]-4 pipéridine et 0,21 g de chlorure de triéthylbenzylammonium dans 100 ml de chloroforme, et de 12,5 g d'hydroxyde de sodium en solution dans 25 ml d'eau. On obtient finalement 3,7 g de chloro-3 méthoxy-6 [(pipéridyl-4) méthyl]-4 quinoléine dont le monochlorhydrate fond au-dessus de 260°C.The procedure is as in Example 1, starting with 10.2 g of [(5-methoxy-indolyl-3) methyl] -4 piperidine and 0.21 g of triethylbenzylammonium chloride in 100 ml of chloroform, and 12.5 g of sodium hydroxide in solution in 25 ml of water. Finally, 3.7 g of 3-chloro-6-methoxy [(piperidyl-4) methyl] -4 quinoline are obtained, the monohydrochloride melts above 260 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,2 - 9 ppm
- - CH3O δ : 4 ppm
- - CH2Ar δ: 3,2 ppm
- - aromatic δ: 7.2 - 9 ppm
- - CH 3 O δ: 4 ppm
- - CH 2 Ar δ: 3.2 ppm
On opère comme à l'exemple 1, en partant de 9,5 g de [(méthyl -7 indolyl-3) méthyl ]4 pipéridine et 0,21 g de chlorure de triéthylbenzylammonium dans 100 ml de chloroforme, et de 12,5 g d'hydroxyde de sodium en solution dans 25 ml d'eau. On obtient finalement 5,1 g de chloro-3 méthyl-8 [(pipéridyl-4) méthyl] -4 quinoléine dont le monochlorhydrate fond à 252°C.The procedure is as in Example 1, starting with 9.5 g of [(methyl -7 indolyl-3) methyl] 4 piperidine and 0.21 g of triethylbenzylammonium chloride in 100 ml of chloroform, and 12.5 g of sodium hydroxide in solution in 25 ml of water. Finally, 5.1 g of 3-chloro-8 [(piperidyl-4) methyl] -4 quinoline is obtained, the monohydrochloride melts at 252 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,3 - 8,8 ppm
- - CH3-Ar δ: 2,8 ppm
- - CH2-Ar δ: 3,2 ppm
- - aromatic δ: 7.3 - 8.8 ppm
- - CH 3 -Ar δ: 2.8 ppm
- - CH 2 -Ar δ: 3.2 ppm
On opère comme à l'exemple 1, en partant de 8,3 g d' (indolyl-2)-2 éthyl]-4 pipéridine et 0,18 g de chlorure de triéthylbenzylammonium dans 90 ml de chloroforme, et de 11 g d'hydroxyde de sodium en solution dans 22 ml d'eau. On obtient 1,45 g de chloro-3 [(pipéridyl-4)-2 éthyl] -2 quino- léine dont le monochlorhydrate fond à 162°C.The procedure is as in Example 1, starting with 8.3 g of (indolyl-2) -2 ethyl] -4 piperidine and 0.18 g of triethylbenzylammonium chloride in 90 ml of chloroform, and 11 g of sodium hydroxide dissolved in 22 ml of water. 1.45 g of chloro-3 [(piperidyl-4) -2 ethyl] -2 quino - leine are obtained, the monohydrochloride melts at 162 ° C.
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7,4 - 8,2 ppm
- - CH2Ar et CH2-N δ: 2,5 - 3,6 ppm
- - aromatic δ: 7.4 - 8.2 ppm
- - CH 2 Ar and CH 2 -N δ: 2.5 - 3.6 ppm
L' [(indolyl-2)-2 éthyl] -4 pipéridine, produit de départ, peut être préparée comme suit[(Indolyl-2) -2 ethyl] -4 piperidine, starting material, can be prepared as follows
A 150 ml d'acide orthophosphorique à 85 %, bien agités, on ajoute progressivement, par portions, 300 g d'anhydride phosphorique, la température étant maintenue inférieure ou égale à 100°C par refroidissement à l'aide d'un bain d'eau. Lorsque le milieu est bien homogène, on introduit 11,4 g d' [(indolyl-3)-2 éthyl]-4 pipéridine, puis on chauffe le milieu réactionnel à 150°C pendant 45 mn. Le liquide sirupeux obtenu est introduit léntement dans 3 kg d'un mélange glace + eau, puis on amène à pH 10 par addition de 800 ml d'une solution aqueuse 11 N d'hydroxyde de sodium. On extrait quatre fois par 300 ml d'acétate d'éthyle. Les extraits sont rassemblés, lavés par 100 ml d'eau, séchés sur sulfate de magnésium et concentrés par élimination de l'acétate d'éthyle. On obtient ainsi 8,2 g d'[(indolyl-2)-2 éthyl] -4 pipéridine, qui fond à 191°C.To 150 ml of 85% orthophosphoric acid, well stirred, is gradually added, in portions, 300 g of phosphoric anhydride, the temperature being maintained less than or equal to 100 ° C by cooling using a water bath. 'water. When the medium is well homogeneous, 11.4 g of [(indolyl-3) -2 ethyl] -4 piperidine are introduced, then the reaction medium is heated to 150 ° C. for 45 min. The syrupy liquid obtained is introduced slowly into 3 kg of an ice + water mixture, then brought to pH 10 by addition of 800 ml of an 11 N aqueous solution of sodium hydroxide. Extraction is carried out four times with 300 ml of ethyl acetate. The extracts are combined, washed with 100 ml of water, dried over magnesium sulphate and concentrated by elimination of ethyl acetate. 8.2 g of [(indolyl-2) -2 ethyl] -4 piperidine are thus obtained, which melts at 191 ° C.
On opère comme à l'exemple 1, en partant de 3,8 g d'[(indolyl-3)-2 éthyl]-3 pipéridine et 0,075 g de chlorure de benzyltriéthylammonium dans 40 ml de chloroforme, et de 5 g d'hydroxyde de sodium dans 10 ml d'eau. On obtient finalement 1,3 g de chloro-3 [(pipéridyl-3)-2 éthyl ] -4 quinoléine, sous forme de monochlorhydrate dihydraté, fondant à 75°C.The procedure is as in Example 1, starting with 3.8 g of [(indolyl-3) -2 ethyl] -3 piperidine and 0.075 g of benzyltriethylammonium chloride in 40 ml of chloroform, and 5 g of sodium hydroxide in 10 ml of water. 1.3 g of chloro-3 [(piperidyl-3) -2 ethyl] -4 quinoline are finally obtained, in the form of monohydrochloride dihydrate, melting at 75 ° C.
L' [(indolyl-3)-2 éthyl] -3 pipéridine, produit de départ, peut être préparée de la manière suivante :
- Sous atmosphère d'azote, on ajoute goutte-à-goutte, à une suspension de 3 g d'hydrure d'aluminium et de lithium dans 500 ml de dioxanne anhydre, une solution de 9,7 g d'indolyl -3 (pipéridyl-3 méthyl) cétone dans 500 ml de dioxanne anhydre. Le mélange est porté au reflux pendant 3 heures, puis on refroidit à O°C et ajoute successivement 15 ml d'eau et 24 ml d'une solution aqueuse d'hydroxyde de sodium à 15 %. Les produits minéraux insolubles formés sont séparés par filtration et le filtrat est séché sur sulfate de magnésium et évaporé. On obtient ainsi 4 g d' [(indolyl-3) -2 éthyl]-3 pipéridine, sous forme d'une huile.
- Under a nitrogen atmosphere, a solution of 9.7 g of indolyl-3 (piperidyl) is added dropwise to a suspension of 3 g of lithium aluminum hydride in 500 ml of anhydrous dioxane -3 methyl) ketone in 500 ml of anhydrous dioxane. The mixture is brought to reflux for 3 hours, then cooled to 0 ° C. and successively added 15 ml of water and 24 ml of a 15% aqueous sodium hydroxide solution. The insoluble mineral products formed are separated by filtration and the filtrate is dried over magnesium sulfate and evaporated. 4 g of [(indolyl-3) -2 ethyl] -3 piperidine are thus obtained, in the form of an oil.
L'indolyl-3 (pipéridyl-3 méthyl) cétone peut être préparée par le procédé décrit dans le brevet français 2 334 358.Indolyl-3 (3-piperidyl methyl) ketone can be prepared by the process described in French patent 2,334,358.
A une solution de 1,8 g de chloro-3 méthoxy-6 [(pipéridyl-4)-2 éthyl ] -4 quinoléine dans 6 ml de chloroforme on ajoute, sous agitation, 6 ml d'une solution aqueuse 1N d'hydroxyde de sodium, refroidie à O°C. On ajoute ensuite, goutte-à-goutte, 0,49 g de chloroformiate d'éthyle. La suspension obtenue est agitée quelques heures, puis décantée. La phase organique est lavée à l'eau, séchée sur sulfate de magnésium, puis concentrée. On obtient ainsi 1,6 g de chloro-3 méthoxy-6 [(éthoxycarbonyl-1 pipéridyl-4)-2 éthyl]- 4 quinoléine sous forme d'une huile.To a solution of 1.8 g of 3-chloro-6-methoxy [(piperidyl-4) -2 ethyl] -4 quinoline in 6 ml of chloroform is added, with stirring, 6 ml of a 1N aqueous hydroxide solution sodium, cooled to 0 ° C. 0.49 g of ethyl chloroformate is then added dropwise. The suspension obtained is stirred for a few hours, then decanted. The organic phase is washed with water, dried over magnesium sulfate, then concentrated. 1.6 g of 3-chloro-6-methoxy [(1-ethoxycarbonyl-4-piperidyl-2) -2 ethyl] - 4 quinoline are thus obtained in the form of an oil.
0,38 g d'hydrure d'aluminium et de lithium sont introduits progressivement, par portions, dans 20 ml de tétrahydrofu- ranne sec, sous atmosphère d'azote. La suspension obtenue est refroidie à 0°C, puis on ajoute, goutte-à-goutte, une solution de 1,6 g de chloro-3 méthoxy-6 [(éthoxycarbonyl-1 pipéridyl-4)-2 éthyl ] -4 quinoléine dans le tétrahydrofu- ranne. Le milieu réactionnel est maintenu 3 heures au bain de glace, puis on ajoute, très lentement et dans l'ordre, 0,45 ml d'eau, 0,33 ml d'une solution aqueuse 5N d'hydroxyde de sodium, et 15 ml d'eau. Les produits minéraux insolubles formés sont séparés par filtration et lavés par deux fois 30 ml de chlorure de méthylène. Le filtrat et les lavages sont rassemblés, séchés sur sulfate de magnésium, puis concentrés par évaporation. Le résidu obtenu est fixé sur une colonne de silice et on élue avec un mélange chloroforme- diéthylamine
Spectre R.M.N. du produit obtenu :
- - aromatiques δ: 7 - 8,7 ppm
- - CH2N et CH2Ar δ: 2,4 - 3,4 ppm
- - CH3O δ: 3,9 ppm ppm
- - aromatic δ: 7 - 8.7 ppm
- - CH2N and CH 2 Ar δ: 2.4 - 3.4 ppm
- - CH 3 O δ: 3.9 ppm ppm
Cette affinité est mesurée par l'aptitude des produits à déplacer le Diazépam tritié (3H Diazépam) de son site de liaison et est exprimée par une valeur K., en micromoles (µM), qui est calculée par la formule :
dans laquelle C représente la concentration de 3H Diazépam, K une constante d'affinité égale à 2,74 µM et IC 50 la concentration nécessaire pour obtenir une inhibition de 50 % de la liaison du 3H Diazépam.in which C represents the concentration of 3 H Diazepam, K an affinity constant equal to 2.74 μM and IC 50 the concentration necessary to obtain a 50% inhibition of the binding of 3 H Diazepam.
Les produits ont été testés selon le protocole de MOHLER et coll., Life Science, 1977, 20, 2101. On a obtenu les résultats suivants :
Les toxicités aiguës des composés selon l'invention ont été déterminées chez la souris mâle CD1 (Charles RIVER) par voie orale. Les DL50 ont été calculés, après 3 jours d'observation, par la méthode cumulative de J.J. REED et H. MUENCH (Amer. J. Hyg. 1938, 27, 493).The acute toxicities of the compounds according to the invention were determined in the male CD 1 mouse (Charles RIVER) orally. The LD50s were calculated, after 3 days of observation, by the cumulative method of JJ REED and H. MUENCH (Amer. J. Hyg. 1938, 27, 493).
Les composés selon l'invention se comportent comme des substances relativement peu toxiques chez la souris, puisque les DL50 des composés se situent entre 200 et 1000 mg/kg.The compounds according to the invention behave like relatively non-toxic substances in mice, since the LD50 of the compounds are between 200 and 1000 mg / kg.
Les composés de l'invention et leurs sels pharmaceutiquement acceptables peuvent être utilisés en thérapeutique humaine, sous forme de comprimés, capsules, gélules, suppositoires, solutions ingérables ou injectables, etc... comme hypnotiques, anticonvulsivants et pour le traitement des états d'anxiété et de divers états psychonévrotiques.The compounds of the invention and their pharmaceutically acceptable salts can be used in human therapy, in the form of tablets, capsules, capsules, suppositories, ingestible or injectable solutions, etc. as hypnotics, anticonvulsants and for the treatment of states of anxiety and various psychoneurotic states.
La posologie dépend des effets recherchés et de la voie d'administration utilisée. Par exemple, par voie orale, elle peut être comprise entre 5 et 250 mg de substance active par jour, avec des doses unitaires allant de 1 à 50 mg.The dosage depends on the desired effects and the route of administration used. For example, orally, it can be between 5 and 250 mg of active substance per day, with unit doses ranging from 1 to 50 mg.
Claims (8)
et l'autre est un groupe de formule :
and the other is a group of formula:
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8005152A FR2477544A1 (en) | 1980-03-07 | 1980-03-07 | NOVEL CHLORO-3 QUINOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS |
FR8005152 | 1980-03-07 |
Publications (2)
Publication Number | Publication Date |
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EP0035925A1 true EP0035925A1 (en) | 1981-09-16 |
EP0035925B1 EP0035925B1 (en) | 1984-12-05 |
Family
ID=9239431
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Application Number | Title | Priority Date | Filing Date |
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EP81400283A Expired EP0035925B1 (en) | 1980-03-07 | 1981-02-24 | 3-chloroquinoline derivatives, processes for their preparation and medicaments containing them |
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Country | Link |
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US (2) | US4405789A (en) |
EP (1) | EP0035925B1 (en) |
JP (1) | JPS56139482A (en) |
AT (1) | AT376217B (en) |
AU (1) | AU540680B2 (en) |
CA (1) | CA1167444A (en) |
DE (1) | DE3167536D1 (en) |
DK (1) | DK101481A (en) |
FR (1) | FR2477544A1 (en) |
NO (1) | NO810776L (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0562832A1 (en) * | 1992-03-23 | 1993-09-29 | Sankyo Company Limited | Indole and indazole derivatives, for the treatment and prophylaxis of cerebral disorders, their preparation and their use |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2495470A1 (en) * | 1980-12-05 | 1982-06-11 | Pharmindustrie | NEW MEDICAMENTS BASED ON (QUINOLYL-4) -1 (PIPERIDYL-4) -2 ETHANOL OR (QUINOLYL-4) -1 (PIPERIDYL-4) -3 PROPANOL DERIVATIVES |
US5240942A (en) * | 1990-07-10 | 1993-08-31 | Adir Et Compagnie | Piperidine, tetrahydropyridine and pyrrolidine compounds |
JP2008545008A (en) * | 2005-06-30 | 2008-12-11 | プロシディオン・リミテッド | GPCR agonist |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2354771A1 (en) * | 1976-06-18 | 1978-01-13 | Mar Pha Etu Expl Marques | ((QUINOLYL-4) -3 PROPYL-1) -4 PIPERIDINES, THEIR PREPARATION AND THEIR USE AS MEDICINAL PRODUCTS |
-
1980
- 1980-03-07 FR FR8005152A patent/FR2477544A1/en active Granted
-
1981
- 1981-02-11 AT AT0063381A patent/AT376217B/en not_active IP Right Cessation
- 1981-02-24 US US06/237,784 patent/US4405789A/en not_active Expired - Fee Related
- 1981-02-24 DE DE8181400283T patent/DE3167536D1/en not_active Expired
- 1981-02-24 EP EP81400283A patent/EP0035925B1/en not_active Expired
- 1981-03-05 CA CA000372413A patent/CA1167444A/en not_active Expired
- 1981-03-06 DK DK101481A patent/DK101481A/en not_active Application Discontinuation
- 1981-03-06 NO NO810776A patent/NO810776L/en unknown
- 1981-03-06 JP JP3237081A patent/JPS56139482A/en active Pending
- 1981-03-06 AU AU68143/81A patent/AU540680B2/en not_active Expired - Fee Related
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1982
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2354771A1 (en) * | 1976-06-18 | 1978-01-13 | Mar Pha Etu Expl Marques | ((QUINOLYL-4) -3 PROPYL-1) -4 PIPERIDINES, THEIR PREPARATION AND THEIR USE AS MEDICINAL PRODUCTS |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0562832A1 (en) * | 1992-03-23 | 1993-09-29 | Sankyo Company Limited | Indole and indazole derivatives, for the treatment and prophylaxis of cerebral disorders, their preparation and their use |
Also Published As
Publication number | Publication date |
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DK101481A (en) | 1981-09-08 |
EP0035925B1 (en) | 1984-12-05 |
AU540680B2 (en) | 1984-11-29 |
FR2477544B1 (en) | 1983-10-21 |
ATA63381A (en) | 1984-03-15 |
US4493838A (en) | 1985-01-15 |
DE3167536D1 (en) | 1985-01-17 |
AU6814381A (en) | 1981-09-10 |
NO810776L (en) | 1981-09-08 |
FR2477544A1 (en) | 1981-09-11 |
US4405789A (en) | 1983-09-20 |
JPS56139482A (en) | 1981-10-30 |
CA1167444A (en) | 1984-05-15 |
AT376217B (en) | 1984-10-25 |
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